The neural correlates of reward processing following acute administration of nicotine in dependent smokers. Smokers and controls underwent fMRI while doing a revised MID task. We saw a significant effect of feedback in the mpfc, striatum and posterior cingulate. The VS showed a significant increase in activation, compared to other losses, when subjects minimized their losses, and a significant decrease, compared to other gains, when they did not maximize their gains. Also, the brain response to a minimum gain was significantly lower than that associated with a minimum loss. No effects of treatment or group and no significant interaction between group and feedback condition were seen. These data suggest activation in striatal regions differentiates between stimuli of differing valence and is relative to predicted or potential outcome. Lack of group differences suggests there is no trait or state effect of nicotine upon this pattern of reward-related activity. Nicotine effects on attention switching. We examined the impact of acute nicotine administration and chronic smoking on neural correlates of attention within a verbal WM task. No drug effects were seen with the TASK or SWITCH effects between nicotine versus placebo. Smokers showed greater activation than controls in medial superior frontal gyrus, left and right middle frontal gyrus, and right insula during task performance. These results suggest that the effects of nicotine on attention may be domain specific, not task-independent. Effects of nicotine on information processing (IP). We sought to determine the relative behavioral and functional effects of acute nicotine on dissociable aspects of IP (i.e. selective attention and motor intention). Nicotine significantly increased the response to intentional primes in brain regions known to mediate response-readiness, e.g. inferior parietal lobe, supramarginal gyrus, and striatum. These data suggest that the behavioral effects of nicotine are not limited to IP but are also generalizable to output functions. Nicotine down regulates default mode networks during attentionally demanding tasks. Nicotine reduced RT in the stimulus detection and selective attention but not divided attention condition. While prefrontal activity partly displayed differential modulation by nicotine, most BOLD effects were identical across tasks, suggesting that common neuronal mechanisms can selectively benefit different attentional functions. Overall, nicotine effects may be explained by increased functional efficiency and down-regulated task-independent "default" functions. Nicotine effects on selected and divided attention. Healthy subjects performed a selective-divided attention paradigm while undergoing fMRI. No region displayed greater activation or deactivation by DIV than the sum of signal change by the two selective attention tasks. Instead, regional activity followed the tasks'processing demands as reflected by RT. These data do not support the existence of brain activity specific to DIV. Smoking reduces white matter integrity and gray matter density in prefrontal cortex. White matter integrity (fractional anisotropy (FA)), revealed lower prefrontal FA levels in highly dependent smokers, and was negatively correlated with FTND score. Gray matter density (GMD) was significantly lower in the PFC in heavy smokers compared to controls and was inversely related to pack years among smokers. Further, the left insular cortex GMD was higher in smokers and was associated with TAS-20-difficulty-identifying-feelings factor. These data suggest that PFC may be altered by chronic smoking while a circuit involving insula and related PFC white matter may reflect stable differences between smokers and controls, possibly related to individual vulnerability to nicotine addiction. Functional and anatomical alterations of anterior cingulate cortex in chronic tobacco smokers. In smokers, the ACC, pfc, right cingulate, occipital gyrus and temporal gyrus showed CBF significantly higher in smoking-related versus neutral cue conditions. The CBF difference between smoking-related and neutral cue conditions in rACC was significantly related to lifetime cigarette usage. The rACC, superior temporal gyrus, pre and post-central gyrus, hippocampus/amygdala, and middle frontal gyrus showed significantly smaller cortical thickness in smokers versus controls. These data suggest that the ACC plays a vital role in nicotine addiction, especially in cue-induced processes. The Neural Basis of Cue-elicited Cigarette Craving and its Control. The aim is to ascertain the neural basis of cue-elicited craving and its control in smokers. The hypothesis is that smokers will, via RT-fMRI biofeedback, be able to modulate activity in their insula, and that this control will lead to better modulation of cue-induced craving that will lead to reduced smoking. Enhanced mesocorticolimbic connectivity influenced by nicotine but not its injection rate. Dependent smokers received 1.5mg of IV nicotine or saline, randomized over 15, 60, or 120s, during separate fMRI scans. Mesocorticolimbic seeds largely showed an increase in connectivity strength after nicotine dosage with enhanced functional connectivity between MD thalamus and medial/superior frontal gyrus and parahippocampal gyrus. Nicotine also increased connectivity between medial frontal gyrus seed and ACC, NAc, insula, and parahippocampal gyrus. BOLD activation in the insula was inversely correlated with FTND, a measure of addiction. Both dACC and medial cingulate revealed this effect through reduced connectivity with the insula. These data suggest nicotine acts to preferentially bias circuits important in addiction such as reward processing and structures heavily populated with acetylcholine receptors. Insula lesions have shown a reduced drive for smoking. Thus, connectivity and activation highlight a region that has been causally implicated in addiction. The connectivity pattern for acute injection appears distinct from that of patch administration. This difference may explain the lack of efficacy seen in using nicotine patch to treat smoking addiction. fMRI Study of Nicotinic Effect on Neurophysiology of Schizophrenia (SZ) (NIDA/MPRC collaboration). We compared behavioral performance and fMRI activation in patients and controls. Data support the idea that SZ patients smoke as a form of self-medication, and suggest that smoking cessation program success will depend on finding alternatives to treat the underlying cognitive deficits. We identified a dorsal anterior cingulate ventral striatum resting state functional connectivity circuit associated with nicotine addiction, which is distinct from other cingulate circuits associated with nicotines pharmacological effect. Nicotine also enhanced sustained attention behavioral performance and neural circuits in patients similar to that of controls. However, this enhancement does not normalize the impaired sustained attention and the associated circuits in SZ patients. Dopamine Function and Reward Processing in Schizophrenia (SZ) (NIDA/MPRC collaboration). We examined brain activity related to reinforcement processing in SZ and the contributions of DA system dysfunction to symptoms. Patients show reduced activity in response to a juice reinforcer in the midbrain, insula, and striatum and reduced differentiation between positive and negative monetary outcomes in multiple brain regions, specifically in areas of mpfc and anterior temporal cortex. Surprisingly, in response to a symbolic reinforcer like money, patients show largely intact neural responses in the striatum.